Interferon mode of action unveiled
Interferons are cytokines used by the immune system as communication signals to trigger protective responses against invading pathogens. Interferon alpha and beta have been exploited for the treatment of hepatitis C and multiple sclerosis (MS) to prevent disease relapse. However, in a significant number of patients, interferon treatment caused neuropsychiatric complications such as depression, anxiety and memory loss. The scope of the EU-funded MBFUSEDIT (Molecular basis for unwanted side-effects during interferon therapy) project was to unravel the cellular and behavioural consequences of IFN-beta treatment to minimise unwanted side effects. In this context, they generated transgenic mice with specific deletion of the receptor for type I interferons (IFNAR) on neurons, macrophages, glia or endothelia in the central nervous system (CNS). Using these mice, researchers set out to delineate how systemically applied IFN-beta mediates its effects in the brain. Gene expression analysis in different brain cell subpopulations indicated that following IFN treatment, endothelial cells underwent the most drastic changes in the expression of interferon-stimulated genes and cytokines. Since brain endothelial cells constitute part of the blood-brain-barrier, researchers speculated that these cells might mediate the IFN side effects. Animals lacking the cytokine IP10 had no signs of depressive-like behaviour after IFN-beta treatment. This supports the hypothesis that IP10 released in response to IFN-beta is responsible for the corresponding behavioural changes. In addition, electrophysiological analysis of the hippocampus indicated that synaptic plasticity was suppressed following IP10 application. Taken together, the observations of the MBFUSEDIT study underscored the importance of brain endothelial cells in the communication between the CNS and the immune system. The engagement of the IFNAR in the cognitive and behavioural impairment during type I IFN therapy opens new roads for the management of these complications.
Keywords
Interferon, immune system, depression, CNS, endothelial cells, IP10
